Medicaments

ABSTRACT

This invention relates to aerosol formulations of use for the administration of medicaments by inhalation. More particularly, the invention relates to a pharmaceutical aerosol formulation which comprises particulate salbutamol sulphate having a crystalline form in which the outer layer of the crystals is substantially non-amorphous; and 1,1,1,2-tetrafluoroethane. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as defined is also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of Ser. No. 09/091,496filed Jun. 18, 1998, now U.S. Pat. No. 6,558,651 allowed, which wasfiled pursuant to 35 U.S.C. §371 as a United States National PhaseApplication of International Application No. PCT/GB96/03154 filed Dec.19, 1996 which claims priority from GB Application No. 9526392.7 filedDec. 22, 1995, the disclosures of which are incorporated herein byreference in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

This invention relates to aerosol formulations of use for theadministration of medicaments by inhalation. More particularly, theinvention relates to aerosol formulations comprising a fluorocarbon orhydrogen-containing chlorofluorocarbon propellant.

Drugs for treating respiratory and nasal disorders are frequentlyadministered in aerosol formulations through the mouth or nose. Onewidely used method for dispensing such aerosol drug formulationsinvolves making a suspension formulation of the drug as a finely dividedpowder in a liquefied gas known as a propellant. The suspension isstored in a sealed container capable of withstanding the pressurerequired to maintain the propellant as a liquid. The suspension isdispensed by activation of a dose metering valve affixed to thecontainer. Devices used for dispensing drugs in this way are known as“metered dose inhalers” (MDI's). See Peter Byron, Respiratory DrugDelivery, CRC Press, Boca Raton, Fla. (1990) for a general background onthis form of therapy.

Patients often rely on medication delivered by MDI's for rapid treatmentof respiratory disorders which are debilitating and in some cases, evenlife threatening. Therefore, it is essential that the prescribed dose ofaerosol medication delivered to the patient consistently meet thespecifications claimed by the manufacturer and comply with therequirements of regulatory authorities. That is, every dose in the canmust be the same within close tolerances.

Some aerosol drugs tend to adhere to the inner surfaces, i.e. walls,valves, and caps, of the MDI. This can lead to the patient gettingsignificantly less than the prescribed amount of drug upon eachactivation of the MDI. The problem has been observed particularly inrelation to formulations comprising salbutamol sulphate andhydrofluoroalkane (also known as simply “fluorocarbon”) propellantsystems, for example 1,1,1,2-tetrafluoroethane, under development inrecent years to replace conventional chloroflurocarbon propellants.

SUMMARY OF THE INVENTION

We have found that using a recrystallised form of salbutamol sulphate,can reduce or eliminate the problem of drug adhesion or deposition andthus ensures consistent delivery of medicament from the metered doseinhaler.

Accordingly, there is provided in one aspect of the invention apharmaceutical aerosol formulation which comprises particulatesalbutamol sulphate having a crystalline form in which the outer layerof the crystals is substantially non-amorphous; and1,1,1,2-tetrafluorethane.

In a further aspect of the invention, there is provided a pharmaceuticalaerosol formulation which comprises particulate salbutamol sulphatehaving a water content of less than about 0.4% by weight; and1,1,1,2-tetrafluoroethane.

In another aspect of the present invention, there is provided apharmaceutical aerosol formulation which comprises particulatesalbutamol sulphate having substantially no thermal activity as measuredby microcalorimetry at about 25° C. and between about 30% to about 90%relative humidity; and 1,1,1,2-tetrafluoroethane.

In yet another aspect of the present invention, there is provided apharmaceutical aerosol formulation which comprises particulatesalbutamol sulphate having reduced thermal activity substantially asshown in FIG. 1; and 1,1,1,2-tetrafluorethane.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The salbutamol sulphate used in the formulations of the presentinvention hereinafter referred to as ‘annealed’ salbutamol sulphate cansuitably be prepared by subjecting particulate salbutamol sulphate to atemperature of between 0° C. to about 100° C. with a relative humidityof between about 20% to about 90%. Alternatively, the salbutamolsulphate can be prepared by subjecting particulate sulphate to elevatedtemperatures, such as about 40° C. to about 100° C. under vacuum.

Whilst not being bound by theory, treating the salbutamol sulphate ineither of the above ways is believed to recrystallise a layer of highenergy or amorphous material on the drug surface to provide a stable,relatively low energy ie, lacks significant thermal activity,crystalline form which has a reduced water content typically of lessthan about 0.4% by weight, referred to as ‘annealed’ salbutamolsulphate. Preferably the salbutamol sulphate employed in theformulations of the present invention will have a water content of lessthan about 0.35% by weight and more preferably less than about 0.3% byweight Particulate salbutamol sulphate, as described in U.S. Pat. No.5,225,183, which has not been so treated has significantly greaterthermal activity and a higher water content normally of about 0.5% byweight or more.

Thus, there is provided in a further aspect of the present invention apharmaceutical aerosol formulation which comprises

(a) particulate salbutamol sulphate obtainable by subjecting saidparticulate salbutamol sulphate to a temperature of between about 0° C.to about 100° C. with a relative humidity of between about 20% to about90%; and

(b) 1,1,1,2-tetrafluoroethane.

In yet a further aspect of the present invention, there is provided apharmaceutical aerosol formulation which comprises

(a) particulate salbutamol sulphate obtainable by subjecting saidparticulate salbutamol to elevated temperatures under vacuum: and

(b) 1,1,1,2-tetrafluoroethane.

Whilst the desired particulate form of salbutamol sulphate (that issubstantially non-amorphous, reduced water content or substantially nothermal activity) has been prepared by the methods described herein, itwill be appreciated that other methods which give salbutamol sulphatehaving said desired characteristics may also be used.

Preferably the annealed salbutamol sulphate employed in the aerosolFormulations of the present invention is obtainable by subjecting theparticulate salbutamol sulphate to a temperature of about 10° C. to 500°C. with a relative humidity of about 55% to about 65%. A temperature ofabout 20° C. to 30° C., for example 25° C., with a relative humidity ofabout 60% is particularly preferred.

Alternatively, the annealed salbutamol sulphate can be obtained byelevated temperatures such as between about 40° C. to about 100° C.,preferably greater than about 60° C., especially greater than about 80°C.

The time required for treating the salbutamol sulphate will naturallydepend upon the amount of drug to be treated, the way in which it ispresented, and the temperature and/or relative humidity selected. Thus,the time required may be from hour(s) to day(s). At lower humiditiesand/or where lower temperatures are used, the time required may belonger, for example, one or more weeks. For manufacturing purposes,shorter treatment times, for example of 1 to 5 hours, are preferred.

To ensure that the micronised salbutamol sulphate is substantiallyuniformly annealed, particularly when large quantities of drug are to betreated, the drug may advantageously be presented such that the surfacearea of drug in contact with the humid and/or warm air is maximised. Forexample, a quantity of drug may be presented in an open tray the base ofwhich comprises a plurality of small apertures to permit access of thehumid and/or warm air to the salbutamol sulphate.

The particle size of the particulate (e.g. micronised) salbutamolsulphate should be such as to permit inhalation of substantially all ofthe medicament into the lungs upon administration of the aerosolformulation and thus will be less than 100 microns, desirably less than20 microns, and preferably in the range of 1 to 10 microns, for example1 to 5 microns.

The final aerosol formulation desirably contains 0.005 to 10% w/w,preferably 0.005 to 5% w/w, especially 0.01 to 1% w/w of salbutamolsulphate relative to the total weight of the formulation. Particularlypreferred are formulations containing 0.05-0.2% w/w of salbutamolsulphate relative to the total weight of the formulation.

The final aerosol formulation may also include one or more adjuvantstypically used in pharmaceutical aerosol formulations. The term‘adjuvants’ as used herein means additives having little or nopharmacological activity (for the quantities used) but which enhance thedrug formulation or the performance of the MDI.

Such adjuvants include alcohols, alkanes, dimethyl ether, surfactants(including fluorinated and non-fluorinated surfactants) carboxylicacids, polyethoxylates and carriers such as sugars, particularlylactose.

Preferred formulations contain an alcohol and/or a surfactant and/or asugar.

An alcohol particularly ethanol may be included in the aerosolformulation, preferably in an amount of 0.01% to 15% w/w, especially0.01% to 5% w/w based on propellant.

Sugars such as lactose may be incorporated in the formulation of thepresent invention, preferably in an amount of 0.0001 to 50% w/w, morepreferably 0.001 to 20%, for example 0.001 to 1% w/w based on the totalweight of the formulation. Generally, the ratio of salbutamol sulphate:sugar falls within the range of 1:0.001 to 1:100 preferably 1:0.1 to1:10. Other sugars which may be used in the formulations include, forexample, sucrose and dextrose. Lactose is, however, preferred.

Surfactants which may desirably be incorporated in the formulation ofthe present invention include both non-fluorinated and fluorinatedsurfactants known in the art, for example, in U.S. Pat. No. 4,352,789,EP0478686 and WO92/00107. Examples of suitable surfactants include oils,derived from natural sources, sorbitan trioleate available under thetrade name Span 85, lecithins derived from natural sources such as thoseavailable under the trade name Epikuron, particularly Epikuron 200,synthetic lecithin, oleic acid, cetyl alcohol and stearyl alcohol.

The surfactants are generally present in amounts not exceeding 5% byweight of the total formulation. They will usually be present in theweight ratio of 1:100 to 10:1 surfactant:salbutamol sulphate, but thesurfactant may exceed this weight ratio in cases where the salbutamolsulphate concentration in the formulation is very low.

Particularly preferred formulations of the present invention, however,are those which are substantially free of surfactant. By‘substantially-free of surfactant’ is meant formulations which containno significant amounts of surfactant ie a non-functional amount, forexample less than 0.0001% by weight of medicament.

Thus, formulations consisting essentially of or consisting of annealedsalbutamol sulphate and 1,1,1,2-tetrafluoroethane form yet a furtheraspect of the present invention.

It will be appreciated by those skilled in the art that the aerosolformulations according to the invention may, if desired, contain acombination of two or more active ingredients. Accordingly the presentinvention further provides aerosol formulations in accordance with theinvention which contain one or more particulate medicaments in additionto salbutamol sulphate. Medicaments may be selected from any suitabledrug useful in inhalation therapy and which may be presented in a formwhich is substantially completely insoluble in the selected propellant.Appropriate medicaments may thus be selected from, for example,analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl ormorphine; anginal preparations, e.g. diltiazem; antiallergics, e.g.cromoglycate, ketotifen or nedocromil; antiinfectives e.g.cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclinesand pentamidine; antihistamines, e.g. methapyrilene; antiinflammatories,e.g. fluticasone, beclomethasone, flunisolide, budesonide, tipredane ortriamcinolone acetonide; antitussives, e.g. noscapine; diuretics, e.g.amiloride; anticholinergics e.g. ipratropium, atropine or oxitropium;hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines e.g.aminophylline, chorine theophyllinate, lysine theophyllinate ortheophylline; and therapeutic proteins and peptides, e.g. insulin orglucagon. It will be clear to a person skilled in the art that, whereappropriate, the medicaments may be used in the form of salts (e.g. asalkali metal or amine salts or as acid addition salts) or as esters(e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise theactivity and/or stability of the medicament and/or to minimise thesolubility of the medicament in the propellant.

Particularly preferred aerosol formulations contain salbutamol sulphatein combination with an antiinflammatory steroid such as a beclomethasoneester (e.g. the dipropionate) or a fluticasone ester (e.g. thepropionate) or an antiallergic such as cromoglycate (e.g. the sodiumsalt). Combinations of salbutamol sulphate and fluticasone propionate orbeclomethasone dipropionate are preferred.

If desirable and appropriate the adjuvants and additional medicamentscan be treated in a similar manner to salbutamol sulphate. That is eachadditional adjuvant or medicament can be treated at differenttemperature/relative humidity combinations as required. Alternatively,the salbutamol sulphate can be admixed with the desired adjuvant and/ormedicament and then treated prior to incorporation in the aerosolformulation.

The formulations of the invention may be prepared by dispersal of theannealed salbutamol sulphate in the selected propellant in anappropriate container, e.g. with the aid of sonication. The process isdesirably carried out under anhydrous conditions to obviate any adverseeffects of moisture on suspension stability.

The chemical and physical stability and the pharmaceutical acceptabilityof the aerosol formulations according to the invention may be determinedby techniques well known to those skilled in the art. Thus, for example,the chemical stability of the components may be determined by HPLCassay, for example, after prolonged storage of the product. Physicalstability data may be gained from other conventional analyticaltechniques such as, for example, by leak testing, by valve deliveryassay (average shot weights per actuation), by dose reproducibilityassay (active ingredient per actuation) and spray distribution analysis.

The particle size distribution of the aerosol formulations according tothe invention is particularly impressive and may be measured byconventional techniques, for example by cascade impaction or by the“twin Impinger” analytical process. As used herein reference to the“twin Impinger” assay means “Determination of the deposition of theemitted dose in pressurised inhalations using apparatus A” as defined inBritish Pharmacopaeia 1988, pages A204-207, Appendix XVII C. Suchtechniques enable the “respirable fraction” of the aerosol formulationsto be calculated. As used herein reference to “respirable fraction”means the amount of active ingredient collected in the lower impingementchamber per actuation expressed as a percentage of the total amount ofactive ingredient delivered per actuation using the twin impinger methoddescribed above. The formulations according to the invention have beenfound to have a respirable fraction of 20% or more by weight of themedicament, preferably 25 to 70%, for example 30 to 60%.

The formulations according to the invention may be filled into canisterssuitable for delivering pharmaceutical aerosol formulations. Canistersgenerally comprise a container capable of withstanding the vapourpressure of the propellant used such as a plastic or plastic-coatedglass bottle or preferably a metal can, for example an aluminium canwhich may optionally be anodised, lacquer-coated and/or plastic-coated,which container is closed with a metering valve.

Aluminium cans which have their inner surfaces coated with afluorocarbon polymer are particularly preferred. Such polymers can bemade of multiples of the following monomeric units: tetrafluoroethylene(PTFE), fluorinated ethylene propylene (FEP), perfluoroalkoxyalkane(PFA), ethylene tetrafluoroethylene (EFTE), vinyldienefluoride (PVDF),and chlorinated ethylene tetrafluoroethylene. The use of suchpolymer-coated cans can help to reduce even further the deposition oradhesion of salbutamol sulphate on the inner surfaces of the can.

The MDI can may be coated by means known in the art of metal coating.For example, a metal such as aluminium or stainless steel may beprecoated as coil stock and cured before being stamped or drawn into thecan shape. Further techniques include spraying the inside of preformedMDI cans with the polymer, dipping preformed cans into the polymer andpouring the polymer inside the MDI cans, followed by curing.Alternatively, the fluorocarbon polymer may be formed in situ usingplasma polymerisation of the fluorocarbon monomers. Fluorocarbonpolymerfilms may be blown inside the MDI cans to form bags. A variety offluorocarbon polymers such as ETFE, FEP, and PTFE are available as filmstock.

The metering valves are designed to deliver a metered amount of theformulation per actuation and incorporate a gasket to prevent leakage ofpropellant through the valve. The gasket may comprise any suitableelastomeric material such as for example low density polyethylene,chlorobutyl, black and white butadiene-acrylonitrile rubbers, butylrubber and neoprene. Suitable valves are commercially available frommanufacturers well known in the aerosol industry, for example, fromValois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300,BK356) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser™).

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method a metering valve is crimped onto an aluminium canto form an empty canister. The annealed salbutamol sulphate is added toa charge vessel and liquefied propellant is pressure filled through thecharge vessel into a manufacturing vessel. The drug suspension is mixedbefore recirculation to a filling machine and an aliquot of the drugsuspension is then filled through the metering valve into the canister.Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

Each filled canister is conveniently fitted into a suitable channellingdevice prior to use to form a metered dose inhaler for administration ofthe medicament into the lungs or nasal cavity of a patient. Suitablechannelling devices comprise for example a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient e.g. a mouthpiece actuator. Metered dose inhalers aredesigned to deliver a fixed unit dosage of medicament per actuation or“puff”, for example in the range of 10 to 5000 microgram medicament perpuff.

Administration of medicament may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient and the frequency ofadministration and will ultimately be at the discretion of the attendantphysician. When combinations of medicaments are employed the dose ofeach component of the combination will in general be that employed foreach component when used alone. Typically, administration may be one ormore times, for example from 1 to 8 times per day, giving for example1,2,3 or 4 puffs each time.

Suitable daily doses, may be, for example in the of 100 to 1000microgram of salbutamol sulphate depending on the severity of thedisease.

Thus, for example, each valve actuation may deliver 100 microgramsalbutamol sulphate. Typically each filled canister for use in a metereddose inhaler contains 100, 160 or 240 metered doses or puffs ofmedicament.

The filled canisters and metered dose inhalers described herein comprisefurther aspects of the present invention.

A still further aspect of the present invention comprises a method oftreating respiratory disorders such as, for example, asthma, whichcomprises administration by inhalation of an effective amount of aformulation as herein described.

The invention is further illustrated but not limited by the followingexamples.

EXAMPLE 1

Micronised salbutamol sulphate (450 g, 2 cm depth) was treated at atemperature of 25° C. at a relative humidity of 60% for 65 hours. Thesalbutamol sulphate was stirred once every 24 hours to enhance exposureto moist air.

To confirm that the salbutamol sulphate had been converted to thedesired low energy, crystalline form i.e. had been annealed, the thermalactivity and the water content of the treated salbutamol sulphatecompared to untreated salbutamol sulphate was measured using standardmicrocalorimetry techniques and moisture sorption techniquesrespectively.

Thermal Activity

A Hart Scientific Microcalorimeter (model 4400) was operated at 25° C.with a water adsorption unit and scanned from about 30% to about 90%relative humidity over a 11.5 hour period. Thermal equilibration timewas 1 to 2 hours.

As shown in FIG. 1, the untreated salbutamol sulphate showed anexothermic rise in heat rate up to approximately 55% relative humidityfollowed by a large endothermic response. This thermal activity wasabsent in the treated salbutamol sulphate, demonstrating that annealinghad occurred.

Water Content

A VTI Corp vacuum balance moisture sorption apparatus (model MB300G) wasoperated at 25° C., and scanned from about 20% to about 90% relativehumidity, total scan time about 15 hours. Drying was accomplished at 35°C. under vacuum for approximately 1 hour before the equilibriumcondition used for the scans of 3 micrograms/6 minutes was achieved.This same equilibrium weight change criterion was used for the sorptionmeasurements.

FIGS. 2 and 3 show the moisture sorption profiles of treated ie annealedand untreated salbutamol sulphate respectively. The figures plot the %weight gain (normalised by the dry weight) against relative humidity at25° C. The untreated salbutamol sulphate exhibits a significantly largermoisture content compared with the treated salbutamol sulphate, clearlydemonstrating that annealing had occurred.

Formulation

Annealed salbutamol sulphate (31.8 mg) was added to1,1,1,2-tetrafluoroethane (19.8 g) in an aluminium alloy canister andthe canister fitted onto a plastic actuator containing the atomisingnozzle to complete the MDI.

Dose delivery from the MDI was tested under simulated use conditions andwas found to be constant compared to control MDIs containing untreatedsalbutamol sulphate which exhibit a significant decrease in dosedelivered through use.

EXAMPLES 2 and 3

Two 7 g batches of salbutamol sulphate were subjected to a temperatureof 25° C. at 85% relative humidity (Example 2) and a temperature of 40°C. at 85% relative humidity (Example 3) for 24 hours.

The thermal activity of the salbutamol sulphate was measured asdescribed in Example 1. The microcalorimetry results are shown in FIG.4. FIG. 4 shows that both batches of salbutamol sulphate lacksignificant thermal activity demonstrating that annealing had occurred.

Annealed salbutamol sulphate (31.8 mg or 15.42 mg) is added to1,1,1,2-tetrafluorethane (19.8 g or 9.6 g respectively) in an aluminiumalloy canister as described in Example 1.

EXAMPLE 4

Micronised salbutamol sulphate (2.2 Kg) is subjected to a temperature of25° C. at a relative humidity of 60% for about 1.5 hours.

Thermal activity of the salbutamol sulphate is measured as described inExample 1. The microcalorimetry data shows that the salbutamol sulphatelacks significant thermal activity demonstrating that annealing hasoccurred.

Annealed salbutamol sulphate (31.8 mg or 15.42 mg) is added to1,1,1,2-tetrafluoroethane (19.8 g or 9.6 g respectively) in an aluminiumalloy canister which has its inner surfaces coated with a fluorocarbonpolymer.

Dose Delivery from the MDIs are tested under simulated use conditionsand are found to be constant compared to control MDIs containinguntreated salbutamol sulphate which exhibit a significant decrease indose delivered through use.

It will be appreciated that modifications to the formulation and themethods described herein can be readily made by a person skilled in theart without departing from the scope of the present invention.Protection is sought for all subject matter described herein includingany such modifications.

What is claimed is:
 1. A process of forming a pharmaceutical aerosolformulation, said process consisting essentially of: subjectingparticulate salbutamol sulphate to a temperature between about 0° C. andabout 100° C. with a relative humidity of between about 20% to about 90%to form annealed particulate salbutamol sulphate; and combining theannealed salbutamol sulphate with a propellant comprising1,1,1,2-tetrafluoroethane to form a pharmaceutical aerosol formulation.2. The process according to claim 1, wherein said step of subjectingparticulate salbutamol sulphate to a temperature of between about 0° C.and about 100° C. with a relative humidity of between about 20% to about90% comprises subjecting particulate salbutamol sulphate to atemperature of between about 10° C. and about 50° C. with a relativehumidity of between about 55% to about 65%.
 3. The process according toclaim 1, wherein said step of subjecting particulate salbutamol sulphateto a temperature of between about 0° C. and about 100° C. with arelative humidity of between about 20% to about 90% comprises subjectingparticulate salbutamol sulphate to a temperature of between about 20° C.and about 30° C. with a relative humidity of about 60%.
 4. The processaccording to claim 1, wherein the annealed particulate salbutamolsulphate is present in the pharmaceutical aerosol formulation in anamount from about 0.01 to about 1% w/w.
 5. The process according toclaim 1, wherein the annealed particulate salbutamol sulphate is presentin the pharmaceutical aerosol formulation an amount ranging from about0.05 to about 0.2% w/w.
 6. The process according to claim 1, thepharmaceutical aerosol formulation consisting essentially of theannealed particulate salbutamol sulphate and 1,1,1,2-tetrafluoroethaneas propellant.
 7. The process according to claim 1, wherein the annealedparticulate salbutamol sulphate is substantially thermally inactive asmeasured by microcalorimetry at about 25° C. and between about 30% toabout 90% relative humidity.
 8. The process according to claim 7,wherein the annealed particulate salbutamol sulphate is micronized andincludes a recrystallized outer layer.
 9. A process of forming apharmaceutical aerosol formulation, said process consisting essentiallyof: subjecting particulate salbutamol sulphate to elevated temperaturesunder vacuum to form annealed particulate salbutamol sulpahte; andcombining the annealed salbutamol sulphate with a propellant comprising1,1,1,1,2-tetrafluoroethane to form a pharmaceutical aerosolformulation.
 10. The process according to claim 9, wherein said step ofsubjecting particulate salbutamol sulphate to elevated temperaturesunder vacuum to form annealed particulate salbutamol sulphate comprisessubjecting particulate salbutamol sulphate to a temperature of fromabout 40° C. to about 100° C.
 11. The process according to claim 9,wherein said step of subjecting particulate salbutamol sulphate toelevated temperatures under vacuum to form annealed particulatesalbutamol sulphate comprises subjecting particulate salbutamol sulphateto a temperature greater than about 60° C.
 12. The process according toclaim 9, wherein the annealed particulate salbutamol sulphate is presentin the pharmaceutical aerosol formulation in an amount from about 0.01to about 1% w/w.
 13. The process according to claim 9, wherein theannealed particulate salbutamol sulphate is present in thepharmaceutical aerosol formulation an amount ranging from about 0.05 toabout 0.2% w/w.
 14. The process according to claim 9, the pharmaceuticalaerosol formulation consisting essentially of the annealed particulatesalbutamol sulphate and 1,1,1,2-tetrafluoroethane as propellant.
 15. Theprocess according to claim 9, wherein the annealed particulatesalbutamol sulphate is substantially thermally inactive as measured bymicrocalorimetry at about 25° C. and between about 30% to about 90%relative humidity.
 16. The process according to claim 15, wherein theannealed particulate salbutamol sulphate is micronized and includes arecrystallized outer layer.